The invention relates to polymorphic crystalline forms of the antihistaminic drug norastemizole and to processes for the production of the preferred polymorph.
Norastemizole, 1-[(4-fluorophenyl)methyl]-N-4-piperidinyl-1H-benzimidazol-2-amine, is an active metabolite of the histamine H1-receptor antagonist astemizole (HISMANAL(trademark)). It is described in U.S. Pat. No. 6,124,320 for use in the treatment of allergic disorders. 
The polymorphic behavior of drugs can be of crucial importance in pharmacy and pharmacology. Polymorphs are, by definition, crystals of the same molecule having different physical properties as a result of the order of the molecules in the crystal lattice. The differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bio-availability). Differences in stability can result from changes in chemical reactivity (e.g. differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g. tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g. tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing: for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (i.e particle shape and size distribution might be different between one polymorph relative to the other).
Each pharmaceutical compound has an optimal therapeutic blood concentration and a lethal concentration. The bio-availability of the compound determines the dosage strength in the drug formulation necessary to obtain the ideal blood level. If the drug can crystallize as two or more polymorphs differing in bio-availability, the optimal dose will depend on the polymorph present in the formulation. Some drugs show a narrow margin between therapeutic and lethal concentrations. Chloramphenicol-3-palmitate (CAPP), for example, is a broad spectrum antibiotic known to crystallize in at least three polymorphic forms and one amorphous form. The most stable form, A, is marketed. The difference in bio-activity between this polymorph and another form B, is a factor of eightxe2x80x94creating the possibility of fatal overdosages of the compound if unwittingly administered as form B due to alterations during processing and/or storage. Therefore, regulatory agencies, such as the US Food and Drug Administration, have begun to place tight controls on the polymorphic content of the active component in solid dosage forms. In general, for drugs that exist in polymorphic forms, if anything other than the pure thermodynamically preferred polymorph is to be marketed, the regulatory agency will require batch-by-batch monitoring. Thus, it becomes important for both medical and commercial reasons to produce and market the most thermodynamically stable polymorph, substantially free of other kinetically favored polymorphs.
From thermodynamic considerations, only one polymorph will be stable; the one with the lowest free energy at a given temperature and pressure. From the industrial crystallization point of view, however, thermodynamic stability is not sufficient to ensure that the stable polymorph will always be produced. During primary nucleation, in the absence of seed crystals, it is the unstable polymorph or pseudo polymorph in the form of a hydrate or solvate that tends to crystallize first (kinetic form). This is, in essence, Ostwald""s Rule of Stages, which posits that an unstable system does not transform directly to the most stable state. Instead, it transforms to a transient state accompanied by the smallest loss of free energy. The eventual transition(s) to the most stable phase is inevitable but the transformation can be extremely fast or extremely slow depending on the process conditions present. Most transformations occur in suspension and are solvent mediated. Some polymorphic transformations can be reversible when the relative solubilities of the polymorphs invert over a range of temperatures (enantiotropic). Other transformations are irreversible (monotropic) over a broad range of temperatures.
Although several syntheses of norastemizole are described in the literature, polymorphism of the solid product is not disclosed. Applicants have now discovered that solid norastemizole exists in two polymorphic forms. As is shown in the results of applicants"" experiments below, the product produced by methods previously described in the literature of which applicants are aware is in every case composed of greater than 80% of the kinetically favored polymorph and less than 20% of the desired thermodynamically stable polymorph. Those references which have been examined include:(1) Janssen et al. U.S. Pat. No. 4,695,569, column 24, lines 22-32;(2) Hong et. al. U.S. Pat. No. 5,817,823, column 32, lines 9-18; column 33, lines 16-23; column 36, lines 31-41; and column 43, lines 19-24; and (3) Maynard et al. U.S. Pat. No. 5,922,737, and column 39, lines 20-30.
In one aspect, the invention relates to norastemizole in the form of a crystalline solid comprising at least 95% of a first polymorph (hereinafter referred to as polymorph A) defined by the X-ray powder diffraction pattern (including both characteristic peaks and intensities) shown below.
This is the more thermodynamically stable polymorph. The kinetically favored polymorph B exhibits an XRPD pattern as follows:
In another aspect, the invention relates to a process for producing crystalline norastemizole, predominantly as polymorph A. In a generic sense the process comprises:
(a) dissolving norastemizole in just enough solvent to achieve dissolution at a first elevated temperature;
(b) adding an amount of anti-solvent just sufficient to initiate crystallization at the first temperature (sufficient means that less than 5% of the norastemizole crystallizes);
(c) stirring the first temperature for a period of time to allow crystallization of a small amount (less than 5%) of the norastemizole; the combination of time and low equilibration of the crystallizing norastemizole to temperature is such as to allow equilibration of the crystallizing norastemizole to greater than 95% polymorph A;
(d) adding a second portion of anti-solvent at the same elevated first temperature and over a second period of time such that norastemizole that crystallizes during the second addition of anti-solvent is greater than 95% of the polymorph of claim 1; to accomplish this, the second portion of anti-solvent is of sufficient amount to produce ultimate crystallization of at least 85% of the norastemizole at a lower temperature, but the amount and rate of addition are kept such that the solubility curve for polymorph B at the temperature of addition is not crossed; and
(e) stirring and cooling from the first, higher temperature to a second, lower temperature in a non-linear fashion over a third period of time such that no more than a 15% temperature drop occurs in the first half of the cooling time; in this fashion, at least 85% of the norastemizole is crystallized and greater than 95% of it is in the form of the polymorph A.
In a particular embodiment of the process aspect, the process comprises: (a) dissolving norastemizole in a solvent at a temperature between 70xc2x0 C. and 110xc2x0 C.; (b) adding an amount of anti-solvent sufficient to initiate crystallization at a temperature above 70xc2x0 C.; (c) stirring at a temperature above 70xc2x0 C. for at least one hour; (d) adding a second portion of anti-solvent at a temperature above 70xc2x0 C. and over a period of at least 2 hours, in an amount sufficient to produce crystallization of at least 85% of dissolved norastemizole; and (e) stirring and cooling from above 70xc2x0 C. to below 30xc2x0 C. over the course of at least 6 hours in a non-linear fashion such that no more than a 15% temperature drop occurs in the first 3 hours.
In another aspect, the invention relates to norastemizole (predominantly in the form of polymorph A) produced by the process described above.
In another aspect, the invention relates to a method for treating allergic conditions in a mammal comprising administering a therapeutically effective amount of norastemizole in the form of polymorph A.
In another aspect, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier for a solid dosage form and norastemizole in the form of polymorph A.